Genetic testing in "Mild Growth Hormone Deficiency".

In their letter to the editor, Tamaro et al. point out that the International Guideline on Genetic Testing suggests an approach for genetic testing in patients with severe growth hormone (GH) deficiency. The authors correctly state that many patients who are diagnosed with “mild growth hormone deficiency” may in fact have alternate explanations for their short stature including genetic etiologies. The international guideline members agree with this comment and do not think it contradicts the guidelines. Many patients who are diagnosed with “mild growth hormone deficiency” are done so based on the results of GH stimulation tests alone, and this diagnosis is often incorrect due to the inaccuracies of stimulation tests. The United States Pediatric Endocrine Society guidelines specifically highlight that the diagnosis of GH deficiency should not be made based on stimulation tests alone.1 In Recommendation 21, we have suggested that the presence of anatomical abnormalities of the hypothalamus/pituitary area should also be an indication for genetic testing. This is an important consideration, as patients with structural hypothalamo-pituitary (HP) abnormalities associated with mutations in some of the genes implicated in HP development may manifest a biochemically milder form of GH deficiency. Mean GH peaks were significantly higher in patients with variants in early developmental genes (SOX2, SOX3, GLI2, LHX3, LHX4, HESX1, OTX2, TCF7L1, FGF8, FGFR1; 2.00 ± 1.79 µg/L), than in patients with variants in genes involved in GH secretion (GH1, GHRHR; 0.95 ± 0.97 µg/L) or in late developmental genes involved in regulating pituitary cell differentiation (PROP1, POU1F1; 0.51 ± 0.58 µg/L) (P = .002).2 The International Guideline on Genetic Testing did not discuss how to accurately make a diagnosis of GH deficiency as this was outside of its scope. The term severe GH deficiency was not meant to imply a specific cut-off based on GH stimulation testing, nor was it meant to imply that patients who in clinical practice are diagnosed with mild GH deficiency should not get genetic testing. Rather, the guideline's diagnostic algorithm highlights that patients with severe GH deficiency require a different genetic testing approach focused on genes involving pituitary development and the GH/IGF-1 axis as opposed to patients with isolated short stature who required a short stature panel which is predominantly focused on genes affecting the growth plate. However, gene variants implicated in Rasopathies can also be associated with GH deficiency and hypopituitarism, suggesting an overlap between the clinical phenotypes of ISS and GHD.3 The guideline members suggest that the majority of patients clinically diagnosed with mild GH deficiency should follow the algorithm for patients with isolated short stature, although mutations in genes such as GH1 (causing Type 2 GHD) and GHSR can be associated with normal GH secretion, even in the face of short stature with clinical GH deficiency.4,5 Stefano Cianfarani: Conceptualization [equal], Writing—review & editing [equal], Andrew Dauber: Conceptualization [equal], Writing—original draft [equal], Mehul T. Dattani: Conceptualization [equal], Writing—original draft [equal], Writing—review & editing [equal], Alexander Jorge: Conceptualization [equal], Supervision [equal], Writing—review & editing [equal], and Jan Wit: Conceptualization [equal], Writing—original draft [equal], Writing—review & editing [equal]. The European Society for Paediatric Endocrinology (ESPE) provided financial support for the project. This covered the costs of the hybrid meeting at which all recommendations were discussed and agreed, as well as publication costs. No payments, honoraria, or travel expenses were made to the authors with respect to the preparation of this manuscript.